Genetic and epigenetic changes that are characteristic of each of the specific stages of skin cancer pathogenesis (initiation, promotion and malignant conversion) have been identified. The Harvey allele of the ras gene family has been Identified as a frequent site for initiating mutations; affected keratinocytes hyperproliferate and are resistant to signals for terminal differentiation. Tumor promoters disturb epidermal homeostasis and cause selective clonal expansion of Initiated cells to produce multiple benign squamous papillomas. The frequency of progression varies among papillomas, and subpopulations at high risk for malignant conversion to squamous cell carcinomas have been identified. These high risk papillomas overexpress the alpha6beta4 integrin. Carcinomas express a splice variant of the alpha6 integrin subunit. High risk papillomas do not express immunodetectable TGF-beta1 or TGF-beta2, and have high levels of basal and suprabasal proliferation. The loss of TGF-beta1 directly contributes to premalignant progression since the introduction of the v-rasHa oncogene Into keratinocytes derived from transgenic mice with a null mutation in the TGF-beta1 gene produces initiated cells that progress rapidly to malignancy when grafted to the backs of nude mice. Accelerated malignant progression Is also found with v-rasHa-transduced keratinocytes from the skin of mice with a null mutation in the p53 gene, and these cells are resistant to growth suppression by,TGF-beta. Using keratinocytes expressing an activated ras gene and overexpressing v-jun and/or v-fos, we have used a differential display procedure to identify 14 AP-1 regulated genes that are differentially expressed in high and low risk tumors. Genetic studies involving crosses between inbred strains that are sensitive (SENCAR A/Pt) and resistant (BALB/c) to skin carcinogenesis have shown that the dominant resistant phenotype Is determined by multiple genes that control sensitivity to promotion.